Drug addiction is associated with persistent alterations in behavior and neurochemistry. This project seeks to identify the behavioral consequences of repeated psychostimulant and opiate use and the neuroadaptations within the brain which underlie their development and long term expression. Previously,we showed that dopamine(DA) uptake and release within the nucleus accumbens are increased during abstinence from cocaine. These changes are thought to underlie the enhanced behavioral responses to cocaine (e.g. sensitization) which occur in experimental animals previously exposed to this agent. Our work has shown that the systemic administration of k-opioid receptor agonists prevents these changes. In animals which have received a k-opioid receptor agonist in combination with cocaine, increases in uptake and release which occur during abstinence are no longer seen. These animals also fail to exhibit sensitization to the psychomotor stimulant effect of cocaine. Such treatment also prevents the the enhancement of cocaine-evoked DA overflow within the nucleus accumbens which occur weeks after the discontinuation of drug use. Mapping studies have shown that the activation of k-opioid receptors in the nucleus accumbens produces these same effects. They prevent the development of cocaine-induced behavioral sensitization and also attenuate cocaine-induced alterations in DA neurochemistry. In contrast, the selective blockade of k-opioid receptors in this brain region exacerbates the behavioral and neurochemical effects associated with repeated cocaine use. The effects of k-opioid agonists infused into the prefrontal cortex are identical to those observed following the blockade of k-receptors in the nucleus accumbens. An augmentation of the behavioral and neurochemical effects of cocaine are seen. These data indicate opposing actions of k-opioid agonists in the mesocortical and mesolimbic DA systems and are consistent with the modulatory role of the prefrontal cortex upon mesolimbic DA neurotransmissionsare. In vitro studies suggest an involvement of the DA transporter and the excitatory amino acid, glutamate, in mediating the cocaine antagonist-like effects of cocaine. Our most recent studies have shown that k-agonist administration also antagonizes the psychomotor stimulant effects of acutely administered amphetamine and antagonizes increases in DA and glutamate release which occur in response to the administration of this psychostimulant. On-going studies seek to determine whether k-agonists modulate the effects of repeated amphetamine or methamphetamine use and the role of k-opioid receptors in other brain regions in mediating the cocaine-antagonist effects of systemically administered k-opioid receptor agonists. Microdialysis studies in genetically manipulated mice lacking MAO B, the vesicular or membrane bound monoamine transporter have also been initiated in order to identify the role of these proteins in the regulation of monoamine release and the neural adaptations which occur as a consequence of cocaine use. Identical studies will be conducted in mice lacking the k-opioid receptor in order to evaluate the involvement endogenous k-opioid systems in modulating the neurochemical and behavioral actions of psychostimulants.